Journal Article

Species-, Sex-, and Cell Type-Specific Effects of Ochratoxin A and B

E. O'Brien, A. H. Heussner and Daniel R. Dietrich

in Toxicological Sciences

Volume 63, issue 2, pages 256-264
Published in print October 2001 | ISSN: 1096-6080
Published online October 2001 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/63.2.256
Species-, Sex-, and Cell Type-Specific Effects of Ochratoxin A and B

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The ubiquitous mycotoxin ochratoxin A (OTA) is associated with the development of urothelial tumors and nephropathies in laboratory animals and in humans with stark species and sex differences with respect to susceptibility in disease development. The mechanism of action remains unknown. OTA-mediated disruptions in normal cell-cycle control could be a major constituent of the mechanisms underlying both its carcinogenic and nephropathy-inducing activities. Assessment of OTA's toxic effects (sum of antiproliferative, apoptotic, and necrotic effects) in rat and porcine continuous cell lines and in primary cells from humans and pigs of both sexes, have displayed a similar sex- and species-sensitivity rank order to that observed in previous in vivo experiments. Furthermore, these toxic effects were observed at nM concentrations in the presence of serum in vitro, thus closely mimicking the in vivo situation. These effects were reversible in all cell types except in human primary epithelial cells of both sexes and did not appear to be primarily dependent on the amount of OTA taken up. Indeed, fibroblasts (NRK-49F) were insensitive to OTA-mediated cell cycle inhibition in spite of accumulating comparable amounts of OTA. The results presented here support the continued use of primary renal epithelial cells for the investigation of the mechanism of OTA-induced carcinogenesis and nephropathy and provide an as-yet preliminary data set that supports the existence of a causal relationship between OTA exposure and human nephropathy.

Keywords: ochratoxin A; nephropathy; renal cancer; uptake; cytostasis; toxicity

Journal Article.  7020 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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